Bacillus anthracis exerts its pathogenic effects through the production of two toxins, lethal toxin and edema toxin. Each of these is a binary toxin consisting of a common subunit, protective antigen (PA), and a unique subunit, lethal factor (LF) or edema factor (EF), respectively. PA is the major bacterial antigen against which the immune system mounts a protective response. The molecular pathogenesis of anthrax involves binding of PA as a heptamer to the host cell, followed by binding of LF or EF and internalization of the complex. Upon endosome acidification, a conformational change in PA allows it to form a pore through which EF or LF enters the cytoplasm and causes disease. Anthrax is treatable with antibiotics only if the infection is identified early in its course. A B. anthracis vaccine is available which elicits antibodies that block PA function, but full immunity requires a long series of injections. With the threat of B. anthracis being used as a bioterrorism weapon, a more rapid-acting vaccine would make immunization of large populations more practicable. Human adenoviruses are DNA viruses that generally cause mild, self-limiting infections in healthy individuals. It is possible to genetically engineer the virus such that its ability to replicate is severely reduced, and to express foreign proteins. As adenovirus is very efficient at infecting antigen presenting cells and inducing immunity, these characteristics make it an excellent choice as a vaccine vector. In the present application, pilot experiments are proposed to assess the feasibility of developing two types of recombinant adenovirus vaccines against PA. The first type will be a replication defective virus that expresses PA as a transgene, and the second will be a virus that expresses specific antigenic domains of PA as part of the virus capsid. Both these vaccines will be tested in a standard routine model of B. anthracis infection. If successful, these initial studies will lead to the development of an improved B. anthracis vaccine, and will establish a platform for similar vaccines against other infectious agents that might be used by bioterrorists.